Neurodegeneration associated with transmissible spongiform encephalopathies (TSE) requires post-translational modification of the cellular prion protein (PrPC) leading to the accumulation of an abnormal protease-resistant isoform (PrPSc or the scrapie isoform of PrPc). The proposed study is a detailed investigation on the roles of loss of PrPc expression and PrPsc aggregation on neurological deficits associated with TSE. Specific aims #1 and #2 will focus on determining whether loss of PrPc function alters hippocampal excitability, NMDA and non-NMDA receptor function, local circuit interactions and synaptic plasticity in the hippocampal dentate gyrus (DG) in vivo in mice devoid of PrPc (PrPNull mice). We will also determine in wild-type (WT) mice inoculated with mouse scrapie the relationship between hippocampal neurophysiology, cognitive function and hypothalamo pituitary-adrenal (HPA) axis regulation. After completion of these experiments, brains will be studied to determine the relationship between CNS function and the development of neuropathology. In collaboration with Dr. Oldstone (Project I), we will study in Specific aim 3 the consequences of deletion of the GPI anchor of PrPc on CNS function in PrP GPI-/- tg mice. We hypothesize the effects of deletion in the GPI anchor on CNS function will resemble our previous findings in PrP null mice. In collaboration with Dr. Williamson (Project II), specific aim 4 will determine the consequences of PrP-specific antibodies and small molecules interacting with regions of PrP on hippocampal DG neurophysiology in vivo. The proposed studies will provide critical information regarding the onset of several neurobehavioral symptoms that precede PrPsc accumulation and neuropathology. These findings will be essential for the development of a sensitive and specific neurobehavioral diagnostic test for the early detection of neurological deficits associated with TSE.